Construction of C-B axial chirality via dynamic kinetic asymmetric cross-coupling mediated by tetracoordinate boron

Catalytic dynamic kinetic asymmetric transformation (DyKAT) provides a powerful tool to access chiral stereoisomers from racemic substrates. Such transformation has been widely employed on the construction of central chirality, however, the application in axial chirality remains underexplored because its equilibrium of substrate enantiomers is limited to five-membered metalacyclic intermediate. Here we report a tetracoordinate boron-directed dynamic kinetic asymmetric cross-coupling of racemic, configurationally stable 3-bromo-2,1-azaborines with boronic acid derivatives. A series of challenging C-B axially chiral compounds were prepared with generally good to excellent enantioselectivities. Moreover, this transformation can also be extended to prepare atropisomers bearing adjacent C-B and C-C diaxes with excellent diastereo- and enantio-control. The key to the success relies on the rational design of a reversible tetracoordinate boron intermediate, which is supported by theoretical calculations that dramatically reduces the rotational barrier of the original C-B axis and achieves the goal of DyKAT.

considerable challenges: (1) the sterically hindered environment around B atom may inhibit the formation of tetracoordinate boron intermediates; (2) it is still uncertain whether the tetracoordinate boron intermediate could really reduce the rotation barrier and facilitate rotation of the aryl group on B atom around the C-B stereogenic axis; (3) competitive intramolecular self-coupling side reactions might occur 69 ; (4) the simultaneous diastereoselective and enantioselective synthesis of axially chiral molecules with multiple axes by one-step reactions is still in its infancy [70][71][72][73][74] .

Results
To validate our hypothesis, we first designed and synthesized racemic 3-bromo-2,1-borazaronaphthalene 1a. Preliminary density functional theory (DFT) calculations were performed to evaluate the feasibilities of the racemization processes of three different species. As depicted in Fig. 2a, substrate 1a with a C-B axis has a rotation barrier of 31.8 kcal/mol to 1a' since the congested steric environment of the planar geometry in transition states induces large distortions of aromatic rings. Compared with 1a, substrate 1a-C for the traditional asymmetric Suzuki-Miyaura coupling possesses not only a shorter C-C axis but also stronger aromaticity, which renders a much higher rotational barrier of 47.8 kcal/mol to 1a-C', making direct dynamic kinetic asymmetric transformation from the substrate (DyKAT) even more unattainable (Fig. 2b). However, the Lewis acidic boronic complex 1a-Pd, the intermediate after oxidative addition of 1a to Pd followed by ligand exchange, allows the coordination of the hydroxide ligand to form a chiral tetracoordinate boron species. In TS-Pd, the tetracoordinate boron species own elongated C-B axis. The corresponding rotational barrier from 1a-Pd to 1a-Pd' is significantly reduced to 16.7 kcal/mol (Fig. 2c), which makes the free rotation of the aryl group around C-B stereogenic axis feasible and fully supports our conjecture. Encouraged by the results from theoretical calculations, we then investigated this envisioned dynamic kinetic cross-coupling using racemic 3-bromo-2,1-borazaronaphthalene 1a and trifluoroborate 2a as model substrates (Fig. 2d). Delightfully, this reaction with Pd 2 (dba) 3 as catalyst, the P-chiral monophosphorus ligand L1 as ligand and Cs 2 CO 3 as base in toluene/H 2 O furnished the desired C-B axially chiral product (R)-3a in 81% NMR yield with 25% enantioselectivity excess (ee) at 40°C (Fig. 2d, entry 1). This result proved the feasibility of our hypothesis and encouraged us to further evaluate other ligands. The P-chiral monophosphorus ligands with small steric hindrance led to higher ee values (Fig. 2d, entries 1-3). The substituents on the aryl units of the ligands have an effect on this reaction (Fig. 2d, entries 4-5), and a better result (Fig. 2d, entry 5, 92% yield and 76% ee) was obtained when ligand L5 with tetrahydrobenzofuran group was used. Subsequently, we investigated the effect of bases and found that these bases all promoted this reaction well, but the enantioselectivities of this reaction were sensitive to bases (Fig. 2d, entries 6-10). In general, weak bases were more favorable for enantioselectivities than strong bases. Overall, the optimized reaction conditions for this DyKAT are shown below: 1a (1 equiv), 2a (1.3 equiv), Pd 2 (dba) 3 (2 mol%), L5 (6 mol%), NaHCO 3 (2 equiv) in toluene/H 2 O at 40°C for 34 h (Fig. 2d, entry 11). In addition, the same yield and enantioselectivity were obtained by reducing the proportion of water when 3-methoxyphenylboronic acid (2a') was used as the substrate (Fig. 2d, entry 12).
To better understand the racemization process of the DyKAT, the following experiments were performed. As illustrated in Fig. 3a, the profile of the ee values or yields of the recovered 1a and the product 3a   versus time indicated that two enantiomers of 1a were consumed together and one of the enantiomers was decreased more rapidly, suggesting a kinetic resolution (KR) process. In addition, the reactions of enantioenriched 1a (37% ee) with two ligands with different configurations were carried out, and the profile of the ee values of the recovered 1a versus time was shown in Fig. 3b. The results also supported a KR process. Finally, no obvious racemization of enantioenriched 3-bromo-2,1-azaborine 1a under standard conditions without aryl trifluoroborates, excluding a dynamic kinetic resolution (DKR) pathway. To demonstrate that the process is indeed a DyKAT, DFT calculations  were performed to probe the mechanism of the racemization process. After oxidative addition and anion ligand exchange, benefiting from the boron Lewis acidity, IM0 first underwent an intramolecular hydroxide migration to form a tetracoordinate boron species IM1 via TS1. The C-B bond in IM1 is free to rotate with a small barrier of 5.2 kcal/mol. The analysis of the geometry of TS2 indicates that owing to the formation of tetracoordinate structure, the naphthalene moiety undergoing rotation is placed on the axial position to avoid repulsions with the benzylic group sprouted on the equatorial position. Meanwhile, the C-B bond is elongated by~0.1 Å, which also provides more space to relax the strain in TS2. Interestingly, IM2 is more stable than its diastereomer IM1 due to the formation of an intramolecular hydrogen bond. The overall energy barrier for the racemization process is 13.8 kcal/mol, endorsing our strategy that the rotation around C-B axis could be realized even with very bulky ligands. Applying the optimized reaction conditions to a range of substrates demonstrates the generality of this DyKAT (Fig. 4). This approach was compatible with aryl trifluoroborate bearing electronrich groups, including alkoxy (3a, 3b, and 3e-3j), methylthio (3c), and N,N-diphenyl (3d), delivering the corresponding C-B axially chiral products in high yields with good to excellent enantioselectivities (80-96% ee). The absolute configuration of (R a )-3a was determined by    X-ray crystallographic analysis (CCDC 2245394, the CIF file is provided in Supplementary Data 1). Aryl trifluoroborate with an electronwithdrawing group was tolerated well under the standard conditions (3k, 70% yield and 93% ee). The tetrastyryl group could also be introduced into the desired product 3l by this method, which provides the possibility for a chiral AIE molecule. Polycyclic aryl trifluoroborates (3m and 3n) and unsubstituted phenyl trifluoroborate (3q) were successfully coupled with excellent enantioselectivities to desired products. Moreover, aryl trifluoroborates bearing heteroaromatic components, including carbazoles (3o and 3p), furan (3r), thiophene (3s), and benzothiophene (3t), could be smoothly converted into the target products with good to excellent enantioselectivities (82-96% ee). Alkenyl trifluoroborates underwent this reaction well, and the better enantioselectivities of 1-substituted alkenyl trifluoroborates (3v and 3w) than (E)-styryl trifluoroborate (3u) may be due to steric hindrance. Next, a wide range of racemic 3-bromo-2,1-borazaronaphthalenes could all undergo this DyKAT to render the corresponding enantiomerically enriched C-B axially chiral molecules (Fig. 5a). Methoxy (3x), methyl (3y and 3ah), and fluoro (3z)-substituted racemic 3-bromo-2,1-borazaronaphthalenes could successfully deliver the desired products in excellent efficiency (77-98% yields and 96-98% ee). Notably, BN-phenanthrene (3aa) was a viable framework for this transformation, providing the corresponding product with excellent enantioselectivity. Moreover, substituents on the N atom of the 2,1-borazaronaphthalene including benzyls (3ab-3ad), n-butyl (3ae), and thiophen-2-ylmethyl (3af) were readily tolerated well. Despite lower yield, the transformation also tolerated bulky (isopropyl) moiety on the N atom of the 2,1-borazaronaphthalene with excellent enantioselectivity (3ag, 33% yield and 97% ee). Low enantioselectivities were obtained when the OMe group was changed to the OEt (3ai) or SEt (3aj) groups with larger steric hindrance.
In view of the successful application of the DyKAT strategy to prepare the C-B axially chiral compounds, we turned our attention to the synthesis of atropisomers with C-B adjacent diaxes of C-B and C-C bonds (Fig. 5b). (2-Methoxy-1-naphthyl)  reaction, and to our delight, the desired axially chiral products 3ak-3an were obtained with excellent diastereoselectivities and enantioselectivities (>20:1 dr, 95-97% ee). The absolute configuration of 3ak was determined by ECD and two-dimensional NMR experiments (for details, see Supplementary Figs. 1-4 and 6-10) 75-77 . This transformation is also applicable to the synthesis of C-B axially chiral compounds bearing complex fragments derived from natural products or therapeutic agents, whose high functional-group compatibility is fully linchpinned. Aryl trifluoroborates derived from clofibrate (4a), estrone (4b), and tyrosine (4c) were transformed into the corresponding C-B axially chiral compounds with ease (Fig. 6a).
In addition, C-B axially chiral compounds could be further modified. Firstly, demethylation of product 3m could generate a C-B axially chiral molecule 5 with free naphthol, which has the potential for further transformations (Fig. 6b). Meanwhile, product 3u could be converted to isopropyl-substituted C-B axially chiral molecule 6 via hydrogenation, and could also react with indole under acid catalysis to afford compound 7 with high retention of the enantiopurity (Fig. 6c).
In conclusion, we developed a palladium-catalyzed DyKAT process of racemic, configurationally stable 3-bromo-2,1-azaborines for the construction of C-B axial chirality. The experiments and calculations demonstrated that the reaction is a DyKAT process and that the reversible tetracoordinate boron intermediate is the key to its success. This chemistry offers practical access to chiral organoborons bearing C-B axis or adjacent C-B and C-C diaxes in generally high yields with excellent diastereoselevtivities and enantioselctivities.

Methods
General procedure for the synthesis of atropisomers with a single C-B stereogenic axis In air, a 25 mL Schlenk tube was charged with 1 (0.1 mmol, 1 equiv), 2 (0.13 mmol, 1.3 equiv), Pd 2 (dba) 3 (2 mol%), L5 (6 mol%), and NaHCO 3 (0.2 mmol, 2.0 equiv). The tube was evacuated and filled with argon for three cycles. Then, 1.5 mL of toluene and 0.3 ml of water was added under argon. The reaction was allowed to stir at 40°C for 34 h. Upon completion, a proper amount of silica gel was added to the reaction mixture. After the removal of the solvent, the crude reaction mixture was purified on silica gel (petroleum ether and ethyl acetate) to afford the desired products.
General procedure for the synthesis of atropisomers with adjacent diaxes of C-B bond and C-C bond In air, a 25 mL Schlenk tube was charged with 1 (0.1 mmol, 1 equiv), 2methoxy-1-naphthyl)boronic acid (1.3-4.0 equiv), Pd 2 (dba) 3 (2 mol%), L5 (6 mol%), and Li 2 CO 3 (2.0-4.0 equiv). The tube was evacuated and filled with argon for three cycles. Then, 1.5 mL of toluene and 0.15 ml of water was added under argon. The reaction was allowed to stir at 40°C for 46-76 h. Upon completion, a proper amount of silica gel was added to the reaction mixture. After the removal of the solvent, the crude reaction mixture was purified on silica gel (petroleum ether and ethyl acetate) to afford the desired products.

Data availability
The data that support the findings of this study are available within the article and its Supplementary Information files. All other data are available from the corresponding author upon request. Supplementary Tables 1 and 2 for mechanism experiment results, Supplementary  Table 3